JP7267244B2 - Compounds for use in skin protection - Google Patents

Description

The present invention provides compounds for use in protecting the skin, methods for preventing or reducing the risk of damage to the skin, and protecting the skin from deterioration due to aging or due to the adverse effects of radiation. Compositions for topical use that relieve, maintain or improve skin properties. In particular, the invention relates to topical compositions containing ketone monoesters and ketone esters for such uses.

Radiation is known to damage living tissues and cells, such as skin. Treatment of the skin to reduce the adverse effects of radiation, particularly ultraviolet (UV) radiation, or deterioration due to aging, is well known.
Much research effort has been devoted to slowing the rate of deterioration or maintaining or improving skin properties, such as skin appearance and feel, and topical compositions for treating skin are has long been known. Dry skin is also a problem for many people. Personal care products such as skin creams and lotions, shampoos, conditioners, toilet bars, shower gels, and antiperspirants, and deodorants typically contain at least one ingredient to combat dry skin. Prescribed. Symptoms such as itching, flaking and an unsightly skin appearance can all be relieved to some extent. A wide range of products have been developed to address these problems, including sealants such as petrolatum or silicone oils that serve to prevent natural water loss. Seals form a barrier between the epidermis and the environment. Keratolytic agents have also been used to speed up skin exfoliation. Alpha hydroxy acids are the most common agents for achieving exfoliation. A further approach consists in the topical application of wetting agents, hydroxylated monomeric or polymeric organic substances typically used for this purpose. Glycerin (glycerol) is well known for this use. Conventional topical applications typically treat the dead superficial layers of the skin primarily and have the advantage of being applied by the user, providing the user with a positive experience of ameliorating the effects of skin condition or aging. obtain.

It is also known to use ingestible ingredients to treat the skin to achieve improvements in skin appearance and texture. These ingredients work by reaching the living interior of the skin. Examples of ingestible ingredients for treating skin include edible fish oils and carotenoids such as lycopene and beta-carotene, which are known to protect against UVR-induced erythema when ingested. Vitamins E and C have also been shown to protect against UVR-induced erythema when taken orally together. Although ingestible treatments can be seen to provide medical benefits, they may not provide the user with an immediate sense of improvement compared to topical compositions.

Including one or more of providing hydration, anti-aging benefits, improving the appearance of the skin, reducing dryness, treating sunburns and the like, and treating medical conditions such as eczema and psoriasis or other above-mentioned problems. There remains a need for compositions that can provide beneficial effects to the skin.
Ketone bodies and ketone body esters are known to reduce the level of circulating free fatty acids in the plasma of patients, as disclosed, for example, in WO2004/105742, and ketone body intake is associated with various clinical effects. can lead to benefits. Ketone bodies are known to treat a wide range of medical conditions, including enhancing cognitive performance, cardiovascular conditions, treating diabetes, and treating mitochondrial dysfunction disorders, as well as treating muscle wasting and dysfunction. It is also known that ketone bodies, as foods, dietary supplements or supplements, or as functional foods, provide beneficial effects, eg, in rehydration.
WO2004/108740 emphasizes oligomers of hydroxybutyrate and a wide range of compounds and compositions containing (R)-3-hydroxybutyrate derivatives that are effective in raising blood levels of ketone bodies. is disclosed. Ketone bodies are produced when fatty acid levels are elevated in the body and are metabolized by the body for energy. In known applications, ketone bodies have been administered to patients enterally or parenterally.

A wide range of ketone bodies containing R-3-hydroxybutyrate are known, including oligomers, oligomeric esters, salts, acid forms thereof, esters of monohydric, dihydric, or trihydric alcohols and their acids. there is However, ketone bodies have been used to date to prevent or reduce the risk of damage to the skin, protect the skin, reduce deterioration of the skin due to aging or due to adverse effects of radiation, or maintain or maintain the properties of the skin. It has not been used topically for remediation.

Dermal fibroblasts are responsible for generating connective tissue and allowing the skin to heal from trauma. Human dermal fibroblasts (HDFs) in culture are primarily dependent on glucose to fuel both aerobic and anaerobic metabolism. The inventors have now found that certain ketone bodies, when applied topically, have beneficial effects on the skin and protect dermal fibroblasts from radiation, especially UV radiation. Ketones also provide beneficial effects for topical application to gums and soft tissues. The user may also experience positive psychological effects associated with the improved properties resulting from the method of topical application of the ketone ester by the user himself.

Live and dead cells after 10 days of incubation Viable cells after 48 hours of UVB exposure

SUMMARY OF THE INVENTION In a first aspect, the present invention provides ketone bodies comprising a (R)-3-hydroxybutyrate moiety for topical use in protecting skin, reducing skin deterioration, or maintaining or improving skin properties. do.
In a second aspect, the present invention is used in a method for protecting skin, reducing skin deterioration, or maintaining or improving skin properties comprising topical application of ketone bodies to the skin. providing said ketone body comprising a (R)-3-hydroxybutyrate moiety for
In a further aspect, the present invention provides a method of protecting, reducing skin deterioration, or maintaining or improving skin properties, wherein a ketone body comprising an (R)-3-hydroxybutyrate moiety is administered to the skin. A method is provided comprising topically applying to

In a further aspect, the present invention provides a ketone body containing an (R)-3-hydroxybutyrate moiety as a topical agent for protecting the skin, reducing skin deterioration, or maintaining or improving skin properties. A use is also provided.
Skin can deteriorate for many reasons, including aging or due to the adverse effects of radiation. The ketone esters of the present invention can reduce the rate of such degradation. Ketone esters containing (R)-3-hydroxybutyrate moieties are particularly useful for protecting human dermal fibroblasts from radiation, such as UV-B radiation. Ketone bodies may be applied to the skin anytime before, during, or after exposure to radiation.
The properties of the skin that can be maintained or improved are one of providing hydration, anti-aging benefits, improving the appearance of the skin, reducing dryness, treating sunburns and the like, and treating medical conditions such as eczema and psoriasis. or including plural.
In a further aspect, the invention provides topical compositions comprising (R)-3-hydroxybutyrate moieties and excipients for topical application. The compositions are suitable for topical use in one or more of protecting the skin, reducing deterioration of the skin due to aging or due to the adverse effects of radiation, and maintaining or improving skin properties.
Preferably, the excipient comprises a cosmetically acceptable carrier.
The present invention also provides a method for improving skin properties comprising topically applying to the skin a composition according to the present invention.

In a further aspect, the invention provides a method of treating skin comprising applying a composition to the skin, wherein the composition comprises (R)-3-hydroxybutyrate moieties and (R)-3-hydroxy Contains excipients for topical application that aid in spreading or absorbing the butyrate portion into the skin.
Advantageously, the ketone bodies and compositions according to the present invention provide beneficial effects on skin properties upon topical application and provide a desirable user experience. Suitably the composition is easily spreadable on and absorbable into the skin, but preferably does not pass through the skin.

The ketone bodies and compositions of the present invention may also be beneficially applied topically to the gums or soft tissue for protection.
While not wishing to be bound by any theory, it is believed that the ketone bodies in the composition are metabolized to generate ATP for energy and nutrients to cells. Conventional skin treatments applied topically use fats and the like to provide a physical effect, ie prevent water from evaporating and thus retain moisture in the dermis. Additionally, conventional topical compositions for improving skin properties are believed to act in a physical manner that exploits the bulk properties of the composition, such as by applying oil or retaining moisture. . However, the inventors have found that using a ketone ester that acts at the cellular level and applying the ketone ester topically achieves a combination of improvements in desirable user experience and skin properties. .

The present invention also provides a method for achieving an anti-aging effect in human or non-human mammalian (preferably human) skin, comprising: an amount of a ketone body according to the present invention effective to achieve said anti-aging effect or applying the composition to the skin of a human or non-human mammal.
As used herein, the term “ketone,” “ketone body,” or “ketone(s)” refers to a compound or species that is a ketone or ketone body precursor, i.e., a precursor to a ketone. and means a compound or chemical species that can be converted or metabolized to a ketone. In preferred embodiments, the ketone body comprises a ketone body ester or a partial ester of a ketone body.

Any ketone body or ketone body ester containing the (R)-3-hydroxybutyrate moiety may be used in the present invention. Preferably, the ketone body comprises a ketone monoester. Examples of suitable ketone bodies or compounds that provide the (R)-3-hydroxybutyrate moiety in situ include oligomers of hydroxybutyrate, triolides, acetoacetate and its esters, and beta Any precursor of hydroxybutyrate is included.
The inventors have surprisingly found that R-3-hydroxybutyl-(R)-3-hydroxybutyrate, a ketone monoester, is metabolized more efficiently than other forms of hydroxybutyrate, especially oligomers. found out.
According to a further aspect of the present invention, R-3-hydroxybutyl-(R)-3-hydroxybutyrate for topical use in protecting skin, reducing skin deterioration, or maintaining or improving skin properties Provided are ketone bodies comprising:
Preferably, the ketone body comprises enantiomerically enriched R-1,3-hydroxybutyl-(R)-3-hydroxybutyrate. R-1,3-hydroxybutyl-(R)-3-hydroxybutyrate monoester may be used in combination with other ketone bodies or ketone body precursors such as acetoacetate. R-1,3-hydroxybutyl-(R)-3-hydroxybutyrate monoester may be present in lesser amounts than any other such ketone body, but preferably any such other ketone present in greater amounts than in the body. In a particularly preferred embodiment, R-1,3-hydroxybutyl-(R)-3-hydroxybutyrate monoester is the only ketone body or ketone body precursor present in the composition of the present invention.

The level of ketone body or ketone body ester in the composition suitably comprises at least 1% ketone body, more preferably at least 10% and up to 95% by weight of the composition. While levels of 15-30% by weight of the composition may be suitable, compositions comprising 30-95%, especially 50-95% by weight of the composition are preferred depending on the skin condition to be treated. be.
Compositions of the invention may further comprise medium chain triglycerides (MCTs) and their related fatty acids. MCTs include fatty acids with chain lengths between 5 and 12 carbon atoms. A diet rich in MCTs is known to increase blood ketone levels. Suitable medium chain triglycerides have the following formula CH ₂ R ₁ -CH ₂ R ₂ -CH ₂ R ₃ where R1, R2 and R3 are fatty acids having 5 to 12 carbon atoms. be. Preferably, MCTs are used in which R1, R2 and R3 are fatty acids containing a 6 carbon skeleton (tri-C6:0).

When MCTs are used, the compositions of the present invention contain i) ketone bodies, preferably ketone monoesters, more preferably D-β-hydroxybutyrate monoesters, ii) MCTs, preferably tri-C6:0MCT and iii) a cosmetically acceptable carrier.
The compositions of the invention may also contain L-carnitine or a derivative of L-carnitine. Examples of derivatives of L-carnitine include decanoylcarnitine, hexanoylcarnitine, caproylcarnitine, lauroylcarnitine, octanoylcarnitine, stearoylcarnitine, myristoylcarnitine, acetyl-L-carnitine, O-acetyl-L- carnitine, and palmitoyl-L-carnitine. When carnitine is used, the compositions of the present invention contain i) a ketone body, preferably a ketone monoester, more preferably D-β-hydroxybutyrate monoester, and ii) L-carnitine or a derivative of L-carnitine. appropriate to include.

If MCT and L-carnitine or a derivative thereof are used, MCT is suitably emulsified with carnitine. Preferably, 10-500 g of emulsified MCT are combined with 10-2000 mg of carnitine, eg 50 g of MCT (95% triC8:0) emulsified with 50 g of mono- and di-glycerides are combined with 500 mg of L-carnitine.

MCTs may be present in greater amounts than ketone bodies, but preferably the levels of ketone bodies are greater than the levels of MCTs.
The compositions may be in solid or liquid form, such as suspensions, dispersions, and emulsions, or other forms known for topical application, such as gels. The compositions, if solid, are suitably made into a form that can be applied topically prior to use, for example by dilution with water, to form pastes, lotions and the like. Preferred forms of compositions include lotions, creams, roll-on formulations, sticks, mousses, aerosol and non-aerosol sprays, and formulations for cloth (eg, nonwoven) application.
The compositions of the present invention are applied to the human body to improve skin properties, including one or more of anti-aging benefits, wrinkle reduction, other aspects of skin appearance, cleansing, deodorizing, or general aesthetics. It may be any substance that Non-limiting examples of suitable compositions include leave-on skin lotions and creams, shower gels, toilet bars, antiperspirants, deodorants, dental products, shaving creams, depilatories, Lipsticks, foundations, mascaras, sunless tanners, and sunscreen lotions.

The cosmetically acceptable carrier can be any known such carrier, used alone or in combination with other carriers. The amount of carrier may range from 1 to 99.9%, preferably from 70 to 95%, optimally from 80 to 90% by weight of the composition. Among the useful carriers are water, emollients, fatty acids, fatty alcohols, thickening agents, and combinations thereof. The carrier can be aqueous, anhydrous, or an emulsion. Preferably, the compositions are aqueous, especially water and oil emulsions of the W/O or O/W or three-phase W/O/W type. Water, if present, may be in an amount ranging from 5 to 95%, preferably from 20 to 70%, optimally from 35 to 60% by weight of the composition.

An emollient material can serve as a cosmetically acceptable carrier. Emollient materials may be in the form of silicone oils, natural or synthetic esters, and hydrocarbons. The amount of emollient may be any value ranging between 0.1-95%, preferably 1-50% by weight of the composition.
Silicone oils can be divided into volatile and non-volatile types. As used herein, the term "volatile" means materials that have a measurable vapor pressure at ambient temperature. Volatile silicone oils are preferably chosen from cyclic (cyclomethicone) or linear polydimethylsiloxanes containing from 3 to 9, preferably from 4 to 5, silicon atoms.

Nonvolatile silicone oils useful as emollient materials include polyalkylsiloxanes, polyalkylarylsiloxanes, and polyether siloxane copolymers. Intrinsically nonvolatile polyalkylsiloxanes useful herein include, for example, polydimethylsiloxanes having viscosities of from 5×10 ^-6 to 0.1 m ² /sec at 25°C. Among the preferred non-volatile emollients useful in the present compositions are polydimethylsiloxanes having viscosities of from 1 x 10 ^-5 to 4 x 10 ^-4 m ² /sec at 25°C.
Another class of non-volatile silicones are emulsifying and non-emulsifying silicone elastomers. Representatives of this class are the dimethicone/vinyl dimethicone crosspolymers available as Dow Corning 9040, General Electric SFE839, and Shin-Etsu KSG-18. Silicone waxes such as Silwax WS-L (dimethicone copolyol laurate) may also be useful.

Suitable ester emollients include:
a) Alkyl esters of saturated fatty acids having 10 to 24 carbon atoms. Examples include behenyl neopentanoate, isononyl isonanonoate, isopropyl myristate, and octyl stearate.
b) Ether-esters, eg fatty acid esters of ethoxylated saturated fatty alcohols.
c) polyhydric alcohol esters, such as ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters Fatty acid esters, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol poly-fatty acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate. , 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are sufficient examples. Particularly useful are pentaerythritol, trimethylolpropane, and neopentyl glycol esters of C1-C30 alcohols.
d) Wax esters such as beeswax, spermaceti and tribehenin waxes.
e) Sugar esters of fatty acids such as sucrose polybehenate and sucrose polycottonseed.

Natural ester emollients are primarily based on mono-, di-, and tri-glycerides. Representative glycerides include sunflower seed oil, cottonseed oil, borage oil, borage seed oil, primrose oil, castor oil and hydrogenated castor oil, rice bran oil, soybean oil, olive oil, safflower oil, shea butter, Jojoba oil, as well as combinations thereof. Animal-derived emollients are represented by lanolin oil and lanolin derivatives. The amount of natural ester may range from 0.1 to 20% by weight of the composition.

Suitable cosmetically acceptable carriers hydrocarbons include petrolatum, mineral oil, C11-C13 isoparaffins, polybutenes, and especially Presperse Inc.; and isohexadecane, commercially available as Permethyl 101A from .
Fatty acids having 10 to 30 carbon atoms may also be suitable as cosmetically acceptable carriers. Examples of this class include pelargonic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid, and behenic acid.
Fatty alcohols having 10 to 30 carbon atoms may also be suitable as cosmetically acceptable carriers. Examples of this class include stearyl alcohol, lauryl alcohol, myristyl alcohol, oleyl alcohol, and cetyl alcohol.

Thickeners can be used as part of the cosmetically acceptable carrier of compositions according to the present invention. Typical thickeners include crosslinked acrylates (e.g. Carbopol 982®), hydrophobically modified acrylates (e.g. Carbopol 1382®), polyacrylamides (e.g. Sepigel 305®), acryloylmethylpropanesulfonic acid /salt polymers and copolymers (eg, Aristoflex HMB® and AVC®), cellulose derivatives, and natural gums. Suitable cellulose derivatives include sodium carboxymethylcellulose, hydroxypropylmethocellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, and hydroxymethylcellulose. Natural gums that are suitable for the present invention include guar, xanthan, sclerotium, carrageenan, pectin, and combinations of these gums. Minerals, particularly clays such as bentonite and hectorite, fumed silica, talc, calcium carbonate, and silicates such as magnesium aluminum silicate (Veegum®) may also be used as thickeners. . The amount of thickening agent may range from 0.0001 to 10%, typically 0.001 to 1%, optimally 0.01 to 0.5% by weight of the composition.

Auxiliary wetting agents may be used in the present invention. These are generally polyhydric alcohol-based materials. Typical polyhydric alcohols include glycerol, propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, isoprene glycol, 1,2,6- Hexanetriol, ethoxylated glycerol, propoxylated glycerol, and mixtures thereof. The amount of co-wetting agent may range anywhere between 0.5 and 50%, preferably between 1 and 15% by weight of the composition.
Surfactants may also be present in the compositions of the invention. The total concentration of surfactants, if present, may range from 0.1 to 90%, preferably from 1 to 40%, optimally from 1 to 20% by weight of the composition and for personal care products. Much depends on the type. Surfactants may be selected from the group consisting of anionic, nonionic, cationic and amphoteric actives. Particularly preferred nonionic surfactants are C10-C20 fatty alcohols or acid hydrophobes condensed with 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobe; mono- and di-fatty acid esters of ethylene glycol; fatty acid monoglycerides; sorbitan, mono- and di-C8-C20 fatty acids; and polyoxyethylene sorbitan, as well as combinations thereof. Alkyl polyglycosides and saccharide fatty amides (eg, methylgluconamide) and trialkylamine oxides are also suitable nonionic surfactants.

Preferred anionic surfactants include soaps, alkyl ether sulfates and sulfonates, alkyl sulfates and sulfonates, alkylbenzene sulfonates, alkyl and dialkyl sulfosuccinates, C8-C20 acyl isethionates, C6- C20 alkyl ether phosphates, C8-C20 sarcosinates, C8-C20 acyl lactates, sulfoacetates, and combinations thereof.
Useful amphoteric surfactants include cocoamidopropyl betaine, C12-C20 trialkylbetaines, sodium lauroamphoacetate, and sodium laurodiamphoacetate.

A sunscreen may also be included in the compositions of the present invention. Particularly preferred are materials such as ethylhexyl p-methoxycinnamate (Parsol MCX®), avobenzene (Parsol 1789®), and benzophenone-3 (also known as oxybenzone). be. Inorganic sunscreen actives such as ultrafine titanium dioxide and zinc oxide may also be used. The amount of sunscreen, if present, may generally range from 0.1 to 30%, preferably from 2 to 20%, optimally from 4 to 10% by weight of the composition.

The antiperspirant and deodorant compositions of the present invention will usually contain an astringent active. Examples include aluminum chloride, aluminum chlorhydrex, aluminum-zirconium chlorohydrex glycine, aluminum sulfate, zinc sulfate, zirconium and aluminum chlorohydroglycinate, zirconium hydroxychloride, zirconium and aluminum lactate, zinc phenolsulfonate. , as well as combinations thereof. The amount of astringent can be anywhere from 0.5 to 50% by weight of the composition.

Preservatives can desirably be incorporated into the personal care compositions of the present invention to protect against the growth of potentially harmful microorganisms. Particularly preferred preservatives are phenoxyethanol, methylparaben, propylparaben, imidazolidinyl urea, dimethyloldimethylhydantoin, ethylenediaminetetraacetate (EDTA), sodium dehydroacetate, methylchloroisothiazolinone, methylisothiazolinone, iodopropynyl butylcarbamate. (iodopropynbutylcarbamate), and benzyl alcohol. Preservatives should be selected with a view to the intended use of the composition and the potential for incompatibilities between the preservative and other ingredients. Preservatives are preferably used in amounts ranging from 0.0001% to 2% by weight of the composition.
The compositions of the invention may also contain vitamins. Exemplary vitamins are vitamin A (retinol), vitamin B2, vitamin B3 (niacinamide), vitamin B6, vitamin C, vitamin E, folic acid, and biotin. Derivatives of vitamins may also be used. For example, vitamin C derivatives include ascorbyl tetraisopalmitate, magnesium ascorbyl phosphate, and ascorbyl glycosides. Derivatives of vitamin E include tocopheryl acetate, tocopheryl palmitate, and tocopheryl linoleate. DL-panthenol and derivatives may also be used. When present in the composition according to the invention, the total amount of vitamins is from 0.001 to 10%, preferably from 0.01% to 1%, optimally from 0.1 to 0.5% by weight of the composition. It may be in the range of % by mass.

Enzymes may be present as desired, such as amylases, oxidases, proteases, lipases, and combinations thereof. Particularly preferred is superoxide dismutase, commercially available as Biocell SOD from Brooks Company, USA.
Skin lightening compounds may be included in the compositions of the present invention. Exemplary substances are placental extract, lactic acid, niacinamide, arbutin, kojic acid, ferulic acid, resorcinol and derivatives including 4-substituted resorcinols, and combinations thereof. The amount of these agents may range from 0.1 to 10%, preferably from 0.5 to 2% by weight of the composition.

Various herbal extracts may be included in the compositions of the invention. Extracts may be either water-soluble or water-insoluble, and are retained in solvents that are hydrophilic or hydrophobic, respectively. Water and ethanol are preferred extraction solvents. Exemplary extracts include those from green tea, chamomile, licorice, aloe vera, grape seed, citrus unshui, willow bark, sage, thyme, and rosemary.

Additional carrier components may be included, such as lipoic acid, retinoxytrimethylsilane (available from Clariant Corp. under the trademark Silcare IM-75), dehydroepiandrosterone (DHEA), and combinations thereof. Ceramides (including ceramide 1, ceramide 3, ceramide 3B, and ceramide 6) and pseudoceramides may also be useful. Amounts of these materials may range from 0.000001 to 10%, preferably from 0.0001 to 1%, by weight of the composition.
Colorants, opacifiers, and abrasives may also be included in the compositions of the present invention. Each of these substances may range from 0.05 to 5%, preferably between 0.1 and 3%, by weight of the composition.
Compositions of the present invention may also be incorporated in an insoluble substrate for application to the skin, such as in the form of treated wipes.

Another aspect of the invention is the inclusion of instructions accompanying or otherwise associated with the packaging in which the ketone bodies or compositions of the invention are supplied. The instructions direct the consumer to use the ketone bodies or compositions topically on the skin, hair, or oral mucosa. The packaging itself will usually be printed along with the instructions, although sometimes a separate written insert within the packaging may serve as the instructions. Typical language includes phrases such as "apply a thin layer to underarms,""apply to hands regularly,""cleanseskin," and "apply a small amount to palms."
The ketone bodies and compositions of the invention are suitable for improving skin properties, in particular for providing anti-aging benefits. By the term "anti-aging" we mean that the skin may be less wrinkled (i.e. wrinkles and/or fine lines have an anti-wrinkle effect, including a reduction in wrinkle depth); The composition reduces dryness, increases firmness, increases elasticity, increases smoothness, improves skin complexion, reduces blemishes, pimples and blemishes (including acne), improves skin complexion, It means that it can provide one or more additional benefits for the skin, selected from reducing skin sensitivity, as well as improving the overall health of the skin.
The ketone bodies and compositions of the invention may exhibit anti-aging effects by improving the nutrition of skin cells or, for example, by increasing collagen synthesis in the skin, and the compositions of the invention increase collagen synthesis. may be used to increase (either as part of the anti-aging effect or separately from the anti-aging effect). Preferably, collagen synthesis is increased by at least 10%, more preferably by at least 20%, such as by at least 25% (eg as determined relative to the mass of collagen preferably synthesized over 14 weeks).

The skin may include the skin of the entire body, preferably the face, neck and/or hands. The skin may also include the scalp as it is beneficial for itching or irritation of the hair (including reducing aging) and scalp.
The following examples are illustrative embodiments of the invention. All parts, percentages and ratios stated herein and in the appended claims are by weight unless stated otherwise.
Various methods of measuring skin characteristics are known to provide a means of judging by an apparent improvement in the measurement or skin characteristics. Examples of such methods include the following.

Measurement of Skin Hydration Various methods for determining the hydration state of the stratum corneum are summarized in Fluhr et al., Skin Res Technol 1999; 5:161-170. Briefly, the Corneometer (Courage & Khazaka) measures skin hydration through the detection of epidermal capacitance. The probe consists of two finger-shaped metal plates close to each other and the depth of measurement is approximately 30 mm. The device determines the wetness level of the outermost skin layer of the stratum corneum. The working principle of the Corneometer® is based on the change in capacitance of the detector, which is designed in the form of a capacitor. The surface of the measuring head, when in contact with the skin, changes capacitance depending on the level of wetting of the skin. An increase in the value measured by Corneometer indicates an improvement in skin hydration.

Measurement of Transepidermal Water Loss (TEWL) An analysis of methods for measuring TEWL is given in Wilson & Maibach, (1989) Transepidermal water loss, A review, In: Cutaneous Investigation in Health and Disease, Noninvasive Methods and Instrumentation (Leveque, JL, ed.), pp. 113-130, Dekker, New York, NY. The skin barrier acts as a regulator in the moisture balance of the skin. If the skin barrier is damaged, the water exchange regulation system becomes unstable. This means that water moves more readily to the external environment, increasing transepidermal water loss. The effectiveness of the skin barrier declines with age. However, when the skin barrier condition improves, water loss is reduced as the water exchange regulatory mechanisms restore their balance. Transepidermal water loss measurements can be performed by Servomed's “Evapometer” EP-3®. A water vapor stream traverses a probe made up of two captors. Measure the partial pressure difference between the two captors. This value corresponds to the evaporation rate of the volatile substance (in this case water). A decrease in TEWL represents an improvement in skin barrier properties.

Skin Elasticity and Firmness Measurements Skin elasticity and firmness measurements were performed using a cutometer and are described in Escoffier et al, J Invest Dermatol, 93(3): 353-7. ing. The measurement is performed with a device that draws up a defined area of the skin surface and optically records it using the principle of vacuum. Analysis of the recorded measurement curves allows the characteristics of skin elasticity and plasticity to be determined. Young skin exhibits a high degree of elasticity and only gradually loses its shape while regaining its original shape after the end of the suction procedure. Young, healthy, supple, well-moisturized skin will have higher elasticity than aged, dry, rough skin. A cutometer therefore provides a series of measurements that can quantify elastic characteristics. This technique consists of aspiration of the skin with a measuring probe. The skin is drawn into the opening of the probe by the negative pressure created within the device. The depth of skin penetration into the probe is measured by a non-contact optical measurement system. The system consists of a light source and photoreceptor, and two prisms facing each other that project the light from the transmitter to the receiver. Light intensity varies with depth of skin penetration. The skin's resistance to wicking is an indicator of its firmness, and its ability to return to its original position is an indicator of its elasticity. At the end of each measurement, a curve is displayed, which allows several calculations to be made, corresponding to the mechanical properties of the skin.

Analysis of Fine Lines, Wrinkles, and Skin Smoothness Skin roughness and wrinkles were measured using replica and skin profilometry as described by Cook, J Soc Cosmet Chem, 1980; 31:339-359. can be evaluated. A silicone rubber material such as Silflo is prepared and applied to the test area. Once set, it is peeled from the skin and analyzed using optical profilometry. With this measurement method, a pattern of parallel stripes is projected onto the skin surface and imaged on the CCD chip of the camera. The 3D measurement effect is achieved due to the fact that minute evaluation differences on the skin surface deflect parallel projection stripes and these deflections constitute a qualitative and quantitative measurement of the skin profile. Skin profiles are recorded by a CCD camera, digitized and transferred to a measurement and evaluation computer for qualitative evaluation.

(Example 1)
Compositions of the Invention Compositions of the invention in the form of cosmetic lotions for topical use are outlined in Table I.

本組成物は、相を連続的に加え、混合物を均質化することによって適切に調製される。

The composition is suitably prepared by successively adding the phases and homogenizing the mixture.

(Example 2)
Compositions of the present invention in the form of skin creams for topical use are shown in Table II.

(Example 3)
Cosmetic compositions of the present invention for topical use are shown in Table III.

(Example 4)
A disposable, single-use personal care wet towel product is described in accordance with the present invention.
A 70/30 polyester/rayon nonwoven towel is prepared with a weight of 1.8 grams and dimensions of 15 cm×20 cm. Onto this wet towel is impregnated a composition having a hydroxybutyrate ester as shown in Table IV below.

(Example 5)
D-beta hydroxybutyrate butanediol monoester was appropriately used in this experiment. The user's hands were inspected prior to application of the D-beta hydroxybutyrate butanediol monoester. Hands had a dry look and feel. D-beta hydroxybutyrate butanediol monoester was applied to the hands and thoroughly massaged into the skin. The hands were inspected again after 30 minutes and observed to have a noticeable visual improvement in properties including less dryness, less wrinkles, and improved feel.

(Example 6)
In this example, the effect of R-3-hydroxybutyl-(R)-3-hydroxybutyrate on proliferation of human dermal fibroblasts was evaluated. Primary human dermal fibroblasts (HDF) with a seeding capacity of 2,500 cells/cm ² from TCS Cellworks were grown in human fibroblast (HF) basal medium (TCS Cellworks) or basal medium containing 4 mM ketone esters. Either delta G was grown in 96-well plates for 24, 48 and 72 hours. Basal medium was replaced daily.

Cell viability was determined using a viability assay kit by two-color fluorescent staining of live and dead cells using the probes Calcein AM and EthD-III. After 10 days of incubation, the number of viable cells is significantly higher (89% vs. 75%, P<0. 05), the number of dead cells was lower. Results are shown in FIG. It can be concluded that the ketone esters according to the invention reduced the death of human dermal fibroblasts.

(Example 7)
Human dermal fibroblasts were cultured in basal medium in 6-well plates at 50,000 cells per well. Cells were incubated with medium alone or medium supplemented with 4 mM R-3-hydroxybutyl-(R)-3-hydroxybutyrate. After reaching 80-90% confluence, the cells were washed with phosphate-buffered saline and the medium was diluted with Hank's buffer, a balanced salt solution designed for use with cells under _CO2- free atmospheric conditions. replaced with layers. At the cellular level, cells were irradiated with doses of 25, 50, 100, 150, 300, and 600 mJ/ ^cm2 using a portable UVB source (302 nm) with a fluence rate of 0.9 mW/ ^cm2 . UV irradiation was performed in a fume hood to maintain sterility. After irradiation, cells were washed and incubated in medium alone or medium plus 4 mM R-3-hydroxybutyl-(R)-3-hydroxybutyrate (as done before irradiation). A separate group of irradiated cells, initially grown in basal medium without delta G, was incubated with 4 mM R-3-hydroxybutyl-(R)-3-hydroxybutyrate. Cell survival was determined by counting viable cells using the trypan blue exclusion method 48 hours after irradiation. The results are shown in FIG.

R-3-hydroxybutyl-(R)-3-hydroxybutyrate protects human dermal fibroblasts from UVB radiation at doses between 150-600 mJ/cm ² when given to the cells after irradiation (p<0.05). Providing R-3-hydroxybutyl-(R)-3-hydroxybutyrate both before and after radiation exposure provided no further advantage.

In summary, R-3-hydroxybutyl-(R)-3-hydroxybutyrate both increased human skin fibroblast viability and protected skin fibroblasts from UV damage.
Another aspect of the present invention may be as follows.
[1] A method of protecting tissue in an animal from damage caused by radiation exposure, comprising contacting said tissue with a therapeutically effective amount of an agent comprising at least one ketone ester, thereby protecting said tissue from radiation damage. A method comprising:
[2] A method for protecting skin, reducing skin deterioration, or maintaining or improving skin properties, comprising a ketone body comprising an (R)-3-hydroxybutyrate moiety, or (R)-3 - topically applying to the skin a composition comprising a ketone body comprising a hydroxybutyrate moiety and an excipient for topical application that aids in spreading or absorbing the (R)-3-hydroxybutyrate moiety into the skin; A method comprising applying to
[3] A method of achieving an anti-aging effect on the skin of a human or non-human mammal, comprising an effective amount of a ketone comprising a (R)-3-hydroxybutyrate moiety to achieve said anti-aging effect. A method comprising applying to the skin of said human or non-human mammal a composition comprising a body or (R)-3-hydroxybutyrate moiety and excipients for topical application.
[4] A ketone body containing an (R)-3-hydroxybutyrate moiety for topical use in protecting the skin, reducing skin deterioration, or maintaining or improving skin properties.
[5] (R) for use in a method for protecting the skin, reducing skin deterioration, or maintaining or improving skin properties, comprising topical application of ketone bodies to the skin; Said ketone body containing a 3-hydroxybutyrate moiety.
[6] The ketone body is selected from oligomers of hydroxybutyrate, triolide, acetoacetate and its esters, acetoacetyl oligomers, and any precursor of beta-hydroxybutyrate that can be metabolized in skin cells, [ 4] or the ketone body according to the above [5].
[7] The ketone body according to any one of [4] to [6] above, which contains 3-hydroxybutyl-(R)-3-hydroxybutyrate.
[8] The ketone according to any one of [4] to [7] above, which contains enantiomerically enriched R-1,3-hydroxybutyl-(R)-3-hydroxybutyrate body.
[9] Use of ketone bodies containing (R)-3-hydroxybutyrate moieties as topical agents to protect the skin, reduce skin deterioration, or maintain or improve skin properties.
[10] A topical composition comprising a (R)-3-hydroxybutyrate moiety and an excipient for topical application.
[11] The topical composition of [10] above, wherein the excipient comprises a cosmetically acceptable carrier.
[12] the above [10] or the above [10] or [ 11].
[13] The topical composition according to any one of [10] to [12], wherein the level of ketone bodies contains at least 1% by mass of ketone bodies.
[14] The topical composition according to any one of [10] to [13], wherein the excipient contains polyethylene glycol.

Claims (4)

Topical use in protecting skin, reducing skin deterioration, or maintaining or improving skin properties containing a ketone body selected from D-beta hydroxybutyrate butanediol monoester and salts of hydroxybutyrate composition for. 2. The composition of claim 1, wherein said ketone body is D-beta hydroxybutyrate butanediol monoester. 3. The composition of claim 1 or 2, further comprising excipients for topical application. Leave-on lotions, leave-on creams, shower gels, bar soaps, antiperspirants, deodorants, dental products, shaving creams, depilatories, lipsticks, foundations, mascara, sunless tanners, or sunscreen lotions A composition according to any one of claims 1 to 3, which is in the form

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